Journal
PLOS GENETICS
Volume 7, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002313
Keywords
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Categories
Funding
- National Institute of Aging (Genetics of Reproductive Life Period and Health Outcomes) [R21AG032598]
- National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]
- National Institute on Aging (NIA) [1RO1AG31206, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, 1R01AG032098-01A1]
- Boston Claude D. Pepper Older Americans Independence Center [5P30AG031679]
- National Institute on Aging and the National Institute of Arthritis Musculoskeletal and Skin Diseases [R01 AR/AG 41398]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities [h1231]
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg - West Pomerania
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg West Pomerania
- Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg - West Pomerania [03IS2061A]
- Siemens Healthcare Diagnostics, Eschborn, formerly DPC Biermann GmbH, Bad Nauheim, Germany
- Swedish Research Council [K2010-54X-09894-19-3, 2006-3832, K2010-52X-20229-05-3]
- Swedish Foundation for Strategic Research [K2010-54X-09894-19-3, 2006-3832]
- ALF/LUA in Gothenburg
- Lundberg Foundation
- Torsten and Ragnar Soderberg's Foundation
- Petrus and Augusta Hedlunds Foundation
- Vastra Gotaland Foundation
- Goteborg Medical Society
- Novo Nordisk foundation
- Canadian Institutes of Health Research [MOP-15261]
- European Commission [HEALTH-F2-2008-201865-GEFOS]
- German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015]
- Helmholtz Center Munich, German Research Center for Environmental Health
- German Federal Ministry of Education and Research (BMBF)
- State of Bavaria
- German National Genome Research Network [NGFN-2, NGFNPlus:01GS0823]
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- National Institutes of Health [HHSN268200782096C]
- NIH, National Institute on Aging
- Netherlands Organisation of Scientific Research NWO [175.010.2005.011, 911-03-012]
- Institute for Diseases in the Elderly [014-93-015
- RIDE2]
- Netherlands Genomics Initiative (NGI) - Netherlands Consortiumof Healthy Aging (NCHA) [050-060-810]
- European Commision [HEALTH-F2-2008-201865, HEALTH-F2-2008-35627]
- Erasmus Medical Center
- Erasmus University Rotterdam
- Netherlands Organisation for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture, and Science
- Ministry for Health, Welfare, and Sports
- the European Commission (DG XII)
- Municipality of Rotterdam
- Italian Ministry of Health [ICS110.1/RF97.71]
- U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]
- National Institute on Aging, National Institutes of Health, Baltimore, Maryland
- Commission of the European Community [QLK6-CT-2001-00258]
- UK Arthritis Research Campaign
- University Hospitals Leuven, Belgium
- Academy of Finland [117797, 121584, 126925]
- Social Insurance Institution of Finland
- Turku University Foundation
- Tampere and Turku University Hospital
- Emil Aaltonen Foundation
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Tampere Tubeculosis Foundation
- Orion-Farmos Research Foundation
- Finnish Foundation of Cardiovascular Research
- Finnish Cultural Foundation
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Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as,300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2x10(-41) and rs6258, p = 2.3x10(-22)). Subjects with >= 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6610216). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
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